Professional Documents
Culture Documents
systemic
inflammatory
response
syndrome.
Extreme of age, both young and old, may not manifest as typical criteria for SIRS;
therefore, clinical suspicion may be required to diagnosis a serious illness (either infectious or
noninfectious). Patients receiving a beta-blocker or a calcium channel blocker are likely
unable to elevate their heart rate and, therefore, tachycardia may not be present.
Although blood pressure is not one of the 4 criteria, it is still an important marker of
possible progression of disease.
SIRS is nonspecific reaction elicited by acute body danger, defensive reaction of the
human body with the goal to localize and eliminate of endogenous or exogenous insults. SIRS
is more complex and more intensive reaction when comparing to the acute phase
reaction. SIRS might lead to complex disturbance of homeostasis with potentially destructive
action the body is affecting itself due to its defensive reaction.
SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or a
combination of several insults. SIRS is not always related to infection. Therefore it is
important to define several terms related to these problems.
SIRS
Sepsis
Bacteriemia
Sepsis induced
hypotension
Septic shock
MODS
SIRS due to severe infection , positive evidence for the presence of bacteria
within the bloodstream, confirmed by cultivation
presence of bacteria within the bloodstream, but this condition does not always
lead to SIRS
the presence of a systolic blood pressure of less than 90 mm Hg or a reduction
of more than 40 mm Hg from baseline in the absence of other causes of
hypotension
clinical syndrome caused by a sepsis, characterized by persistent hypotension
and perfusion abnormalities (mostly in microcirculation), despite adequate
fluid and vasopressoric resuscitation
Multiple organ dysfunction syndrome dysfunction of kidneys, liver, lungs,
heart, GUT caused by a severe hypo perfusion, and other complications of
SIRS physiological derangements in which organ function is not capable of
maintaining homeostasis
D: Causes of SIRS
The most common causes of SIRS related to infectious disease are as follows:
bacterial infection, wound infection (burns, surgical wounds, diabetic foot and other
infectious complications), cholecystitis, cholangoitis, other abdominal infections, pneumonia
both nosocomial or community acquired, urogenital infections, meningitis and other less
frequent conditions
Noninfectious causes as underlying conditions for SIRS involve acute intestinal ischemia,
pancreatitis, GUT bleeding, autoimmune diseases, burns, aspiration, cirrhosis, inadequate
reaction to drugs, cocaine, amphetamines, teophyllin in high dose, myocardial infarction,
trauma and other causes.
Pathophysiology
SIRS, independent of the etiology, has the same pathophysiologic properties, with minor
differences in inciting cascades. Many consider the syndrome a self-defense mechanism.
Inflammation is the body's response to nonspecific insults that arise from chemical, traumatic,
or infectious stimuli. The inflammatory cascade is a complex process that involves humoral
and cellular responses, complement, and cytokine cascades. Bone best summarized the
relationship between these complex interactions and SIRS as the following 3-stage process:
Stage I: Following an insult, local cytokines are produced with the goal of inciting
an inflammatory response, thereby promoting wound repair and recruitment of the
reticular endothelial system.
Stage II: Small quantities of local cytokines are released into circulation to
improve the local response. This leads to growth factor stimulation and the
recruitment of macrophages and platelets. This acute phase response is typically well
controlled by a decrease in the proinflammatory mediators and by the release of
endogenous antagonists. The goal is homeostasis.
Stage III: If homeostasis is not restored, a significant systemic reaction occurs.
The cytokine release leads to destruction rather than protection. A consequence of
this is the activation of numerous humoral cascades and the activation of the reticular
endothelial system and subsequent loss of circulatory integrity. This leads to endorgan dysfunction.
E: Initiation of SIRS
Trauma, inflammation, or infection leads to the activation of the inflammatory
cascade. When SIRS is mediated by an infectious insult, the inflammatory cascade is often
initiated by endotoxin or exotoxin. Tissue macrophages, monocytes, mast cells, platelets, and
endothelial cells are able to produce a multitude of cytokines. The cytokines tissue necrosis
factor-
(TNF-
) and interleukin (IL)1 are released first and initiate several cascades. The
release of IL-1 and TNF-
(or the presence of endotoxin or exotoxin) leads to cleavage of the
nuclear factor-
B (NF-
B) inhibitor. Once the inhibitor is removed, NF- B is able to
initiate the production of mRNA, which induces the production other proinflammatory
cytokines. If the SIRS is induced by viral infection the main stimulus is interferon gamma
IFN released from cells infected and destroyed by the virus.
IL-6, IL-8, and interferon gamma are the primary proinflammatory mediators
induced by NF- B. In vitro research suggests that glucocorticoids may function by inhibiting
NF- B. TNF-
and IL-1 have been shown to be released in large quantities within 1 hour of
an insult and have both local and systemic effects. In vitro studies have shown that these 2
cytokines given individually produce no significant hemodynamic response but cause severe
lung injury and hypotension when given together. TNF-
and IL-1 are responsible for fever
and the release of stress hormones (norepinephrine, vasopressin, activation of the reninangiotensin-aldosterone system).
The figure shows activation of NFkB, primary transcriptive factor preexisting in the
cytoplasm like an inactive molecule linked to the inhibitor complex subunit. The answer to
external stimuli or presence of lipopolysacharide is the cleavage of the inhibitory subunit,
transport into the nucleus and initiation of transcription of target genes.
Other cytokines, especially IL-6, stimulate the release of acute-phase reactants such as
C-reactive protein (CRP). Of note, infection has been shown to induce a greater release of
TNF-
than trauma, which induces a greater release of IL-6 and IL-8. This is suggested to be
the reason higher fever is associated with infection rather than trauma.
The proinflammatory interleukins either function directly on tissue or work via secondary
mediators to activate the coagulation cascade, complement cascade, and the release of nitric
oxide, platelet-activating factor, prostaglandins, and leukotrienes.
Numerous proinflammatory polypeptides are found within the complement cascade.
Protein complements C3a and C5a have been the most studied and are felt to contribute
directly to the release of additional cytokines and to cause vasodilatation and increasing
vascular permeability. Prostaglandins and leukotrienes incite endothelial damage,
leading to multiorgan failure.
The correlation between inflammation and coagulation is critical to understanding
the potential progression of SIRS. IL-1 and TNF-
directly affect endothelial surfaces, leading
to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby
promoting coagulation, and is a proinflammatory mediator itself. Fibrinolysis is impaired by
IL-1 and TNF-
via production of plasminogen activator inhibitor-1. Proinflammatory
cytokines also disrupt the naturally occurring anti-inflammatory mediator's antithrombin and
activated protein-C (APC). If unchecked, this coagulation cascade leads to complications of
microvascular thrombosis, including organ dysfunction. The complement system also plays a
role in the coagulation cascade. Infection-related procoagulant activity is generally more
severe than that produced by trauma. The cumulative effect of this inflammatory cascade is an
unbalanced state with inflammation and coagulation dominating.
this blood pool is not adequately completed from the marrow pool proliferation and
maturation might be not so strong enough to stabilize normal WBC count
Respiratory Dysfunction
Pulmonary dysfunction is common in the patient with SIRS and is manifested as
tachypnoea, hypoxaemia and respiratory alkalosis. When severe it may progress to acute lung
injury (ALI) and acute respiratory distress syndrome (ARDS). The primary pathological
process is pulmonary capillary endothelial dysfunction resulting in interstitial and alveolar
oedema of protein and phagocytic immune cell rich exudative fluid. Endothelial permeability
is increased in response to pro-inflammatory cytokines with progression to alveolar
denudation and basement membrane destruction. Another mechanisms employed are
destruction of pneumoctyes type I, destruction of surfactant molecules, and onset of
microatelectatic areas in lungs.
Cardiovascular Dysfunction
Both the heart and the blood vessels are sensitive to the effects of pro-inflammatory cytokines
as well as vasoactive substances present in excessive amounts in SIRS. Nitric oxide is
synthesized by inducible nitric oxide synthasis (ions) from L-argentine in the vascular
endothelium and smooth muscle in response to pro-inflammatory cytokines. Nitric oxide is
the vocative mediator responsible for the fall in systemic vascular resistance underlying the
hypotension in SIRS. This hypotension may be refractory to treatment with fluids, inotropes
and conventional vasoconstrictors.
The response to the fall in blood pressure is an increase in cardiac output. Baroreceptors
mediate a pronounced tachycardia and stroke volume increases due to decreased afterload but
hypovolaemia may decrease preload and thus cardiac output. Independent of the effects of
preload and afterload intrinsic myocardial depression is present within 24 hours of the onset
of SIRS. Endotoxin and pro-inflammatory cytokines have both been shown to induce
myocardial depression. These effects are probably mediated through nitric oxide. Constitutive
NO in the heart is responsible for leucitropy, the ability of the myocardium to relax, thus
maximizing end diastolic filling and coronary artery perfusion. Inducible NOS is expressed in
cardiac myocytes in response to cytokines and increases NO production. Nitric oxide reduces
myocardial contractility and responsiveness to b-adrenergic agents mediated through
increased cGMP.
Renal Dysfunction
Several mechanisms have been proposed for the pathogenesis of acute renal failure occurring
in SIRS. In normal states, the kidney maintains renal blood flow and glomerular filtration
through autoregulation dependent on the tone of the afferent and efferent arterioles, an autoregulation is disturbed in SIRS. The cytokine-induced systemic vasodilatation and relative
hypovolaemia in SIRS are responsible for renal hypoperfusion. Therefore, it is difficult to
predict renal blood flow from systemic blood pressure parameters. The kidney produces
intrinsic vasoconstrictors in response to cytokines and the renin-angiotensin-aldosterone
system. In particular, the arachidonic acid metabolites of thromboxane and leukotrienes both
reduce renal blood flow and antagonists of these substances have been shown to have renal
protective effects. In common with other tissues, the kidney is susceptible to leucocyte
mediated tissue injury with neutrophil aggregation in response to chemokines and production
of proteases and ROSs.
GIT
Gastrointestinal system suffers from hypoperfusion too; and the barrier function of the
intestinal wall is compromised due to hypoperfusion. After that a translocation of intraluminal
bacteria or their endotoxin might occur worsening the homodynamic parameter primarily
disturbed due to SIRS. There is a possibility for the development of septic complication in
patients with SIRS as a response to no infection causes based on the mechanisms of
bacterial translocation across the impaired intestinal barrier from the lumen into the internal
environment.
Metabolic Disturbances
The alteration in haemodynamic regulation produces inappropriate distribution of perfusion
and arteriovenous shunting resulting in tissue hypoxia and lactic acidosis. Many of the current
therapeutic approaches aim to optimize oxygen delivery to the tissues by improving perfusion
and avoiding hypoxemia. The cellular hypoxia is confounded due to impaired cellular oxygen
extraction. Evidence suggest this is at a mitochondrial level mediated through NO which
blocks the mitochondrial electron transfer chain at its terminal receptor of cytochrome
oxidase. This then causes cellular hypoxia and an increase in mitochondrial derived ROS
concentrations.
Haematological Dysfunction
SIRS is often associated with a disorder of coagulation secondary to the cytokine-mediated
activation of the coagulation pathways. This disseminated intravascular coagulation (DIC)
produces both bleeding and microvascular thrombi which have been proposed as mechanisms
of multiorgan dysfunction. The cytokine-mediated activation of coagulation in SIRS occurs
via the tissue factor dependent extrinsic pathway. Tissue factor is the activator of and cofactor
for factor VIIa activation of factors IX and X of the extrinsic pathway.
Monocytes and endothelial cells express tissue factor in response to endotoxin, complement
fractions, IL-6 and IL-8. Attenuation of the anticoagulant systems furthers the procoagulant
state. Antithrombin III (ATIII) is an inhibitor of the serine proteases responsible for
coagulation clotting factors IXa, Xa, XIa and XIIa and thrombin. Thrombomodulin is an
endothelial cell derived inhibitor of clotting and activator of fibrinolysis. It acts as a thrombin
binding protein, reducing the effects of thrombin. The thrombin-thrombomodulin complex
has further anti-coagulant properties as an activator of protein C which, with cofactor protein
S, inactivates factors V and VIII. In sepsis, the production of thrombomodulin by endothelial
cells is downregulated by pro-inflammatory cytokines and circulating free levels of protein S
are reduced.